Influence Of Immunosuppressive Agents Research Articles

The influence of immunosuppressants on direct-acting antiviral therapy is dependent on the hepatitis C virus genotype.

Direct-acting antivirals (DAAs) have substantially increased sustained virological response rates after liver transplantation, with improved tolerance compared to interferon-based therapy. The influence of immunosuppressive agents on the efficacy of DAAs has not been clarified. Subgenomic hepatitis C virus (HCV) replicons for genotype (GT) 1b, 2b, 3a, and 4a were treated with the mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus or with the calcineurin inhibitors (CNIs) cyclosporine or tacrolimus, either alone or in combination with selected DAAs. Cell proliferation-related effects were excluded with MTT assays. HCV replication activity was quantified by quantitative real-time polymerase chain reaction or luciferase assay. Addition of either mTOR inhibitor to the DAA daclatasvir (DAC) resulted in a 30% increase in antiviral activity compared to DAC alone for HCV GT2a, GT3a, and GT4a (all P≤.01). Similar results were obtained using sofosbuvir and ledipasvir. In contrast, addition of either mTOR inhibitor to DAC induced a 30% reduction in antiviral activity in GT1b cells (P≤.01 vs DAC alone). Neither CNI affects the antiviral activity of the DAAs in any HCV GT. For patients with HCV GT2a, GT3a, or GT4a infection, mTOR-based immunosuppressive therapy may be beneficial. CNI-based therapy may be more efficacious in GT1b patients, as mTOR inhibitors seem to impair antiviral efficacy of DAAs in HCV GT1b infection.

The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients

Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.

The influence of therapy on CD4+CD25highFOXP3+ regulatory T cells in systemic lupus erythematosus patients: a prospective study

Objectives: Regulatory T cells (Tregs) are inversely correlated to disease activity in systemic lupus erythematosus (SLE). However, little is known concerning the influence of immunosuppressive agents on Tregs, which was the objective of this study.Method: Thirty-five patients with SLE (29 females, six males, mean age 42.4 ± 12.8 years) were included. CD4CD25highFOXP3 Tregs were prospectively assessed by flow cytometry every month for intravenous (iv) and quarterly for oral regimens. Clinical assessment was made with the SLE Disease Activity Index (SLEDAI). Statistical analysis was performed with a Student’s t-test; p < 0.05 was considered significant.Results: In total, 44 cases of SLE relapse were treated with iv cyclophosphamide (CYP, n = 10), iv methylprednisolone (MP, n = 7), iv immunoglobulins (IVIGs, n = 5), oral MP (n = 8), oral MP  azathioprine (AZA, n = 8), and hydroxychloroquine (HCQ, n = 6). CYP, iv MP, and IVIGs resulted in a significant increase in Tregs (4.2 ± 1.6 vs. 10.1 ± 5.7, 2.9 ± 1.3 vs. 10.6 ± 4.8, and 5.6 ± 2.7 vs. 15.2 ± 6.3 cells/mm3, respectively, p < 0.05). Oral MP, alone or combined with AZA, led to a significant increase in Tregs (7.4 ± 2.5 vs. 11.8 ± 3.8 and 5.1 ± 2.4 vs. 9.4 ± 3.6 cells/mm3, respectively, p < 0.05), as did HCQ (8.2 ± 2.4 vs. 12.8 ± 2.7 cells/mm3, p < 0.05). Time to Tregs recovery was significantly shorter with iv MP and IVIGs compared to CYP (1.4 ± 0.5, 1.6 ± 0.9, and 4.0 ± 1.5 months, respectively, p < 0.05).Conclusions: Increase in Tregs during SLE remission is independent of the therapeutic regimen used and probably represents an epiphenomenon of disease remission. Time to Tregs restoration was significantly shorter in patients treated with iv MP and IVIGs compared to CYP pulse therapy.

AB0492 The Influence of Therapy on CD4+Cd25highfoxp3+ T Regulatory Cells in Systemic Lupus Erythematosus Patients: A Prospective Study

BackgroundT regulatory cells (Tregs) are inversely correlated to disease activity in systemic lupus erythematosus (SLE). However, little is known concerning the influence of immunosuppressive agents on Tregs and their kinetics,...

Vaccinations in juvenile chronic inflammatory diseases: an update

Vaccination is a powerful tool to reduce the burden of infectious diseases in paediatric patients with chronic rheumatic diseases. Live attenuated vaccines are not recommended for profoundly immunosuppressed patients, but nonlive vaccines have adequate safety and efficacy profiles in the few (admittedly underpowered) studies published to date. No severe vaccine-specific or disease-specific adverse events have been observed in patients with juvenile idiopathic arthritis (JIA) or childhood-onset systemic lupus erythematosus (SLE) who have been vaccinated with live or nonlive agents. The immune response to live vaccines is variable in these patients but generally adequate, despite concomitant use of immunosuppressive and biologic agents. The proposal that onset of autoimmune rheumatic diseases could be induced by vaccination is controversial and primarily based on case reports; however, patients with mevalonate kinase deficiency can experience febrile attacks after immunizations. Adequately powered studies of live and nonlive vaccination in patients with paediatric rheumatic diseases are necessary to clarify safety and efficacy issues. This narrative Review discusses vaccination in patients with JIA, childhood-onset SLE, juvenile dermatomyositis, juvenile systemic sclerosis, primary vasculitis and autoinflammatory syndromes. Vaccine safety, short-term and long-term changes in disease parameters, and the immunogenicity and influence of immunosuppressive agents are outlined for each combination of disease and vaccine.

The influence of immunosuppressive agents on BK virus risk following kidney transplantation, and implications for choice of regimen

The increasing incidence of BK-associated nephropathy following kidney transplantation has prompted an examination of strategies for risk reduction and management through immunosuppression manipulation. Evidence from retrospective and prospective studies suggests that BK viruria and viremia, and the need for BK virus treatment, are higher with tacrolimus than cyclosporine. Combined therapy with tacrolimus and mycophenolic acid may be associated with a particularly higher risk of BK infection, but data are conflicting as to whether mycophenolic acid per se is an independent risk factor. The incidence of BK-related events may be reduced in patients receiving mTOR inhibitors (everolimus or sirolimus) with cyclosporine vs a calcineurin inhibitor with mycophenolic acid. De novo immunosuppression regimens that avoid rabbit antithymocyte globulin and tacrolimus, particularly tacrolimus with mycophenolic acid, may be advantageous, whereas low-exposure cyclosporine with an mTOR inhibitor appears a favorable option. Routine screening for BK infection during the first 2 years posttransplant is recommended to allow preemptive modification of the immunosuppressive regimen. In patients at high risk of BK virus infection, appropriate de novo immunosuppression or very early conversion to an mTOR inhibitor to facilitate reduction or discontinuation of calcineurin inhibitors or antimetabolites should be considered. Extensive further research into optimal avoidance, screening, and treatment strategies is required.

Influence of immunosuppressive agents on tryptophan degradation and neopterin production in human peripheral blood mononuclear cells

The anti-proliferative and immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) degrades the essential amino acid tryptophan via the kynurenine pathway. IDO is stimulated during cellular immune responses preferentially by Th1-type cytokine interferon-γ (IFN-γ). IDO activity is estimated by calculating the kynurenine to tryptophan ratio (Kyn/Trp). In human monocyte-derived macrophages and dendritic cells, GTP-cyclohydrolase I is induced in parallel to IDO and produces neopterin.This study investigated the effects of common immunosuppressants on freshly isolated human peripheral blood mononuclear cells (PBMC) in vitro. PBMC were incubated with compounds for 30min and then either left unstimulated or stimulated with mitogen phytohaemagglutinin (PHA). Concentrations of tryptophan, kynurenine and neopterin were measured in supernatants after 48h.Kyn/Trp, neopterin and IFN-γ concentrations were significantly higher in PHA-stimulated vs. unstimulated PBMC. Tacrolimus (FK506), cyclosporine A (CsA), sirolimus and methylprednisolone dose-dependently inhibited tryptophan degradation and neopterin production. FK506, CsA and sirolimus showed significant inhibition at concentrations as low as 0.1μg/ml, whereas prednisolone and methylprednisolone required higher doses to suppress tryptophan degradation. Mycophenolate-mofetil suppressed neopterin formation more efficiently than Kyn/Trp. All tested drugs also strongly decreased mitogen-induced IFN-γ concentrations.Overall the investigated immunosuppressants are effective to inhibit IDO activity and neopterin production in a similar and dose-dependent manner, however with some differences in IC50s when comparing individual compounds. The corresponding changes of IFN-γ concentrations are in line with its role as a trigger of both biochemical changes.

Controlling the Generation and Function of Human CD8+ Memory T Cells In Vitro with Immunosuppressants

Memory T cells play a pivotal role in acute and chronic rejection of transplanted organs. Novel therapies such as alemtuzumab and the identification of heterologous memory have highlighted their importance following transplantation. Unlike naive T cells, the influence of immunosuppressive agents on the de novo generation of memory T cells and on the function of pre-existing memory T cells is poorly understood. CD8 effector memory T cells (Tem, CD45RA, CCR7) were generated by stimulating peripheral blood mononuclear cells for five days with anti-CD3 and anti-CD28 monoclonal antibodies, followed by nine days of rest. The influence of immunosuppression on this was assessed by flow cytometry. Tem that had been naturally formed in vivo were used to study the influence of the same agents on the function (intracellular interferon-gamma production) of Tem cells. Whereas all the immunosuppressive agents tested inhibited the expansion of CD8 Tem population by influencing their proliferation and apoptosis, the calcineurin inhibitors were better at controlling their function. Furthermore, Tem generated despite the presence of tacrolimus were functional and did not exhibit drug resistance. Immunosuppressive agents differ in their ability to control the generation and function of CD8 Tem; the calcineurin inhibitors being the most efficacious. This may be of importance when tailoring immunosuppressants for transplant recipients, particularly in those where there is pre-existing immunological memory or in those receiving T-cell depleting therapies, which skews the immune repertoire towards memory.

Surfactant as a carrier: influence of immunosuppressive agents on surfactant activity

It has been proposed that exogenous pulmonary surfactant can be used as a drug delivery system for immunosuppressive agents to the alveolar compartment of the lung while reducing the risk of systemic toxicity. Before using this combination, however, alterations in activity of both substances should be examined. Therefore, this study investigated whether the activity of a natural derived surfactant preparation is changed after it is mixed with cyclosporine A (CsA) or rapamycin (RPM). A surfactant suspension was mixed with CsA or RPM and minimal surface tension of these mixtures was measured in vitro. Surfactant activity was evaluated in vivo by its capacity to restore gas exchange in an established model of surfactant deficiency in rats. CsA-surfactant, RPM-surfactant or surfactant alone was instilled intratracheally and blood gases were measured under standardized ventilatory conditions. Minimal surface tension of surfactant-CsA was comparable with that of surfactant alone, whereas minimal surface tension of the surfactant-RPM mixture was increased. In vivo partial arterial oxygen pressure levels increased immediately to prelavage values after instillation of CsA-surfactant, RPM-surfactant and surfactant only and were comparable during the entire study period. The activity of a naturally derived surfactant was affected when mixed with RPM but not when mixed with CsA at the used concentrations.

Influence of immunosuppressive agents on magnesium (Mg) metabolism after allogeneic hematopoietic stem cell transplantation (HSCT): Comparison between cyclosporine a (CSA) and tacrolimus

Influence of immunosuppressive agents on magnesium (Mg) metabolism after allogeneic hematopoietic stem cell transplantation (HSCT): Comparison between cyclosporine a (CSA) and tacrolimus

Quality of life in kidney recipients: comparison of tacrolimus and cyclosporine-microemulsion.

Treatment of end-stage renal disease (ESRD) is evaluated by survival, quality of life (QOL) and cost-effectiveness. Little is known about the influence of immunosuppressive agents on global and disease-specific QOL in kidney recipients. In winter 1997/98 (t0) as well as in winter 1998/99 (t1), all kidney recipients of our University were asked to participate in a QOL study. The psychodiagnostic approach combined a global QOL-measure (SF-36 Health Survey) and a disease-specific questionnaire (ESRD-SCL, Nephron 1999). Inclusion criteria for the final analysis were (a) participation in both surveys and (b) eligibility after the matching procedure: patients with tacrolimus-based immunosuppressive regimen were matched to patients with cyclosporin-microemulsion (CsA-ME)-based immunosuppressive-regimen as to age, gender and duration of graft function. Group data were compared by performing a two-variate ('immunosuppression', 'time') analysis of variance. Both groups consisted of 63 patients. Analysis of QOL revealed statistically significant advantages for the tacrolimus treated patients concerning global (SF-36 'Physical Component Summary') as well as disease-specific QOL (ESRD-SCLTM 'Global Severity Index'; both p < 0.05). In detail, these results were due to statistically significant better QOL in tacrolimus treated patients as to the SF-36 subscales 'Physical Functioning' and 'General Health' (p < 0.05) and the ESRD-SCL subscales 'Limited Physical Capacity' (p < 0.05), 'Cardial and Renal Dysfunction' (p < 0.01) and 'Increased Growth of Gum and Hair' (p < 0.001). The factor 'time' did not contribute statistically significant to explanation of variance. In terms of QOL in kidney recipients, tacrolimus is superior to CsA-ME. Tacrolimus improves disease-specific QOL and also shows slight advantages concerning global QOL compared with CsA-ME. To record differentiated aspects of QOL in kidney recipients, the diagnostic approach should include a global QOL measure completed by a sensitive disease-specific instrument.

T cell rosette formation in primates, pigs, and guinea pigs: The influence of immunosuppressive agents

Out of 144 combinations of lymphocytes from 8 species and erythrocytes from 18, significant numbers of rosettes were found in only 14. Human and chimpanzee lymphocytes formed rosettes in the greatest number of combinations (5), pig lymphocytes with 3, and guinea pig lymphocytes with only one erythrocyte (rabbit). In all positive combinations tested, the percentage of rosette-forming cells was highest in the thymus, intermediate with lymph node and peripheral blood lymphocytes, and lowest in the spleen. Using the guinea pig rosette-forming cell as an experimental test for T lymphocytes, the effect of several immunosuppressive drugs on the percentage of lymphocytes that are T cells was measured. Cyclophosphamide injected into guinea pigs increased this percentage the most, cortisone and tilorone increased the percentage of rosette-forming cells slightly, and azathioprine and vinblastine caused no change. After in vitro incubation with the lymphocytes, cyclophosphamide, azathioprine, and tilorone increased the percentage of rosette-forming cells and vinblastine reduced this percentage.